Co-administration of a prostaglandin and an androgenic agent in the treatment of female sexual dysfunction

ABSTRACT

Methods and formulations for treating female sexual dysfunction are provided. A pharmaceutical composition formulated so as to contain a selected vasoactive agent is administered to the vagina, vulvar area or urethra of the individual undergoing treatment. Suitable vasoactive agents are vasodilators, including naturally occurring prostaglandins, synthetic prostaglandin derivatives, endothelial-derived relaxation factors, vasoactive intestinal polypeptide agonists, smooth muscle relaxants, leukotriene inhibitors, and others. The formulations are also useful for preventing the occurrence of yeast infections, improving vaginal muscle tone and tissue health, enhancing vaginal lubrication, and minimizing excess collagen deposition. A clitoral drug delivery device is also provided.

CROSS-REFERENCE TO RELATED APPLICATIONS

This is a continuation of U.S. Ser. No. 09/539,484, filed Mar. 30, 2000,now U.S. Pat. No. 6,306,841, which was a continuation of U.S. Ser. No.09/181,316, abandoned, filed Oct. 27, 1998, which was acontinuation-in-part of both U.S. Ser. No. 08/959,064, filed Oct. 28,1997, now U.S. Pat. No. 5,877,216, and U.S. patent application Ser. No.08/959,057, also filed Oct. 28, 1997, now abandoned, the disclosures ofwhich are hereby incorporated by reference.

TECHNICAL FIELD

This invention relates generally to methods and pharmaceuticalformulations for treating female sexual dysfunction, and moreparticularly relates to vaginal, vulvar and/or urethral administrationof a vasoactive agent, such as a prostaglandin, in such treatment. Theinvention further relates to additional methods of using the presentpharmaceutical formulations, including, but not limited to, theprevention of yeast infections and the improvement of vaginal muscletone.

BACKGROUND

Sexual response in women is generally classified into four stages:excitement, plateau, orgasm, and resolution. Masters and Johnson, HumanSexual Response (Boston, Mass.: Little, Brown & Co., 1966). With sexualarousal and excitement, vasocongestion and muscular tension increaseprogressively, primarily in the genitals, and is manifested by increasedblood flow, elevated luminal oxygen tension, and vaginal surfacelubrication as a result of plasma transudation that saturates the fluidreabsorptive capacity of the vaginal epithelium. Vasoactive intestinalpolypeptide (“VIP”) release may induce the physiological changes ofsexual arousal and excitement, and may be the major neurotransmitterthat participates in the innervation of the vaginal blood supply.Peptide histidine methionine has been co-located with VIP within nervefibers that innervate small blood vessels, smooth muscle and epithelialcells in the vaginal tract.

Sexual excitement is initiated by any of a number of psychogenic orsomatogenic stimuli and must be reinforced to result in orgasm. Withcontinued stimulation, excitement progresses in intensity into a plateaustage, from which the individual can shift into orgasm. The orgasmicstage is characterized by a rapid release from vasocongestion andmuscular tension.

During the various stages of sexual response, characteristic genital andextragenital responses occur. Estrogens magnify the sexual responses;however, sexual responses may also occur in estrogen-deficientindividuals. Sexual dysfunction may be due to organic or functionaldisturbances. For example, a variety of diseases affecting neurologicfunction, including diabetes mellitus and multiple sclerosis, mayinterrupt sexual arousal. More commonly, local pelvic disorders, such asendometriosis and vaginitis, both of which cause dyspareunia (difficultor painful coitus) may also affect a woman's sexual response. Inaddition, estrogen deficiency, causing vaginal atrophy and dyspareunia,is a common cause of sexual dysfunction. For a discussion of othercauses of female sexual dysfunction, see, e.g., Kaplan, The Evaluationof Sexual Disorders: Psychological and Medical Aspects (New York:Brunner-Mazel, 1983), and Kolodny et al., Textbook of Sexual Medicine(Boston, Mass.: Little, Brown & Co., 1979).

Excitement stage dysfunction generally involves touch sensationimpairment, loss of clitoral sensation, vaginal dryness and urinaryincontinence. Such excitement phase dysfunction generally results indyspareunia. Dyspareunia is thought to affect approximately 40% ofwomen, due in large part to inadequate lubrication. It has beenestimated that over 40 million women will suffer dyspareunia at sometime in their lives. On the order of twenty-five million will experiencedyspareunia in the peri- and postmenopausal period (see Kelly, S. (1992)Clinical Practice and Sexuality 8(8):2 and Sato et al. (1992) ClinicalPractices in Sexuality 8(5):1). Contemporary symptomatic treatmentsgenerally involve the use of physiologically safe lubricants such as eggwhite, K-Y surgical lubrication jelly (hydroxyethyl-cellulose),Astroglide®, and Replens®. See, for example, Semmens (1974) MedicalAspects of Human Sexuality 8:85-86, and Frishmen et al. (1992) Fertilityand Sterility 58(3):630. When symptomatic treatment fails,pharmacological treatment may be indicated.

Estrogen therapy is commonly used in the pharmacological treatment ofsexual dysfunction in women. Estrogen-based therapies are generally usedto increase mucous production, provide vasodilatory effects, or toincrease the general health of the vagina. Nadelson et al., eds.,Treatment Interventions in Human Sexuality (New York: Plenum Press,1983). In such treatments, estrogen is administered orally, parenterally(e.g., by injection), or topically. With oral administration, theestrogen concentration encountered by the liver is generally four- tofive-fold greater than estrogen levels in peripheral blood (the “firstpass effect”). This effect may lead to an undesirable increase in theproduction of certain coagulation factors and renin substrates by theliver. Parenterally administered estrogen avoids the first pass effectin the liver. However, all estrogen-based therapies are known toincrease the risk of endometrial hyperplasia endometrial cancer andbreast cancer in treated individuals.

Because of the increased risk of endometrial hyperplasia and endometrialcancer encountered with unopposed estrogen therapies,estrogen/progestogen combinations have been employed. However,progestogens are known to have some androgenic activity. Further, commonside effects from such therapies include uterine bleeding and thecontinuation of menstrual periods. Accordingly, there remains a need inthe art to provide safer and more ways of treating female sexualdysfunction.

The present invention is directed to the aforementioned need in the art,and provides a new, highly effective method of treating sexualdysfunction in women. The method involves vaginal, vulvar and/orurethral administration of a pharmaceutical formulation containing avasoactive agent, e.g., a prostaglandin or the like.

Drug therapy for treating female sexual dysfunction has been described.For example, U.S. Pat. No. 4,507,323 to Stern describes the use of theanxiolytic m-chloro-α-t-butylamino-propiophenone in the treatment ofsexual dysfunction in both male and female individuals. Pharmaceuticalcompositions containing the agent are described, which are presented indiscrete units, e.g., cachets, tablets, capsules, ampules andsuppositories, for oral or rectal delivery of the agent.

Additionally, U.S. Pat. No. 4,521,421 to Foreman describes the treatmentof sexual dysfunction in male and female individuals using thestereoisomers of octahydropyrimido[4,5-g]quinolines, centrally actingdopamine agonist.

U.S. Pat. No. 5,190,967 to Riley describes the treatment of sexualdisorders in male and female individuals using heterocyclicbenzodioxinopyrrole compounds, which, like the drugs described in theaforementioned patents, are centrally acting agents.

U.S. Pat. Nos. 5,565,466 to Gioco et al., 5,731,339 to Lowrey, and5,773,457 to Nahoum pertain to methods for modulating the human sexualresponse, with the Gioco et al. and Lowrey patents emphasizing theutility of phentolamine as an active agent.

A number of references describe various methods and devices suitable forvaginal or uterine drug administration, and may accordingly be of someinterest with respect to the present invention. The following arerepresentative of such references:

U.S. Pat. No. 3,967,618 to Zaffaroni describes an intrauterine deviceadapted for drug delivery. A number of drugs are mentioned as beingsuitable for use in conjunction with the device. However, the patentdoes not mention treatment of sexual dysfunction, nor is application ofa drug-containing composition to the clitoris, vulvar area or urethradisclosed or suggested. U.S. Pat. No. 3,948,254 to Zaffaroni is arelated patent that describes an intrauterine device for continuousadministration of a contraceptive agent.

U.S. Pat. No. 4,014,987 to Heller et al. describes a tampon-like devicefor delivery of a drug to the uterus or vagina. Heller et al. mentionthat delivery of prostaglandins is a preferred use of the invention;however, there is no disclosure concerning treatment of sexualdysfunction or delivery to the vulvar area or urethra.

U.S. Pat. No. 4,564,362 to Burnhill describes a vaginal sponge forcontrolled release of a contraceptive agent.

U.S. Pat. No. 3,800,038 to Rudel describes a method and composition foruterine administration of steroid hormones. Prostaglandins such as PGE₁are mentioned as useful in conjunction with the invention. However,there is no disclosure concerning vaginal drug delivery, urethral drugadministration, application of a drug-containing formulation to theclitoris or surrounding vulvar area, or treatment of sexual dysfunction.

U.S. Pat. No. 4,961,931 to Wong describes a vaginal drug administrationdevice adapted to deliver contraceptive hormones, includingprogestational and estrogenic hormones.

U.S. Pat. No. 4,112,942 to Scaife generally describes vaginaladministration of medicinal foams.

The vaginal delivery of prostaglandins in connection withcontraceptives, labor and delivery has also been described. U.S. Pat.No. 4,976,692 to Atad describes the uterine administration of acomposition containing PGE₂ and triacetin gel in priming the cervixbefore induction of labor.

Vaginal PGE₂ suppositories (“Prostin E2®”) and a cervical gel containingPGE₂ (“Prepidil”® gel), both manufactured by Upjohn (Kalamazoo, Mich.),are commercially available. See, e.g., Physicians'Desk Reference®, 51stEdition (Montvale, N.J.: Medical Economics Data Production Company,1997). The suppositories are primarily indicated for evacuation ofuterine contents, while the gel is used in connection with induction oflabor.

U.S. Pat. Nos. 4,818,517 to Kwee et al., 4,680,312 to Johnson, 4,454,339to Skuballa et al. and 4,128,577 to Nelson each relate to vaginaladministration of prostaglandins. However, these patents focus on theuse of prostaglandins in contraceptives, labor and delivery, and do notpertain to treatment of female sexual dysfunction.

U.S. Pat. No. 4,254,145 to Birnbaum relates to the use ofprostaglandins, including natural and synthetic analogues ofprostaglandin types PGE, PGA and PGE_(β), in the treatment ofarteriospastic and occlusive peripheral vascular disorders as well as inthe treatment of impotency. The described methods of treatment involvetopical administration or localized injection of pharmaceuticalcompositions containing the exemplified prostaglandins to increaseperipheral circulation. The compositions are also described for use inlowering systemic blood pressure. Although a number of therapeuticapplications are described, the patent does not suggest treatment offemale sexual disorders using vaginal, vulvar or urethral delivery ofprostaglandins.

Several references are also of interest herein insofar as they pertainto urethral drug administration to treat sexual dysfunction in men,e.g., vasculogenic impotence or the like. See, for example, U.S. Pat.Nos. 5,242,391, 5,474,535, 5,686,093 and 5,773,020 to Place et al. andU.S. Pat. No. 4,801,587 to Voss et al., which relate to the treatment oferectile dysfunction by delivery of a vasoactive agent into the mateurethra.

There are, accordingly, a number of background references relating totreatment of female sexual dysfunction, cervical or uterineadministration of prostaglandins, and urethral drug administration inmen. However, the present method for treating female sexual dysfunction,by way of vaginal, vulvar and/or urethral delivery of a vasoactive agentsuch as a prostaglandin, is completely novel and unsuggested by the art.

SUMMARY OF THE INVENTION

Accordingly, it is a primary object of the invention to provide a methodfor treating sexual dysfunction in a female individual by administeringa pharmaceutical formulation containing a selected vasoactive agent tothe vagina, vulvar area or urethra of the individual undergoingtreatment.

It is still another object of the invention to provide methods forpreventing the occurrence of yeast infections, for improving vaginalmuscle tone and tissue health, for enhancing vaginal lubrication, andfor minimizing collagen misdeposition resulting from hypoxia, each ofsuch methods involving vaginal, vulvar and/or urethral administration ofa pharmaceutical formulation containing a selected vasoactive agent, incombination with a pharmaceutically acceptable vehicle.

It is a further object of the invention to provide pharmaceuticalformulations useful in conjunction with the aforementioned methods.

It is still a further object of the invention to provide a drug deliverydevice for administering a pharmaceutical formulation directly to theclitoral area.

Additional objects, advantages and novel features of the invention willbe set forth in part in the description that follows, and in part willbecome apparent to those skilled in the art upon examination of thefollowing, or may be learned by practice of the invention.

In one aspect of the invention, then, a method is provided for treatingsexual dysfunction in a female individual comprising administering tothe vagina, vulvar area or urethra a pharmaceutical formulationcontaining a selected vasoactive agent. The vasoactive agent ispreferably a vasodilator, with preferred vasodilators selected from thegroup consisting of naturally occurring prostaglandins, syntheticprostaglandin derivatives, endothelial-derived relaxation factors,vasoactive intestinal polypeptide agonist, smooth muscle relaxants,leukotriene inhibitors, pharmaceutically acceptable salts, esters,analogs, derivatives and inclusion complexes thereof, and combinationsof any of the foregoing. Any number of drug delivery platforms may beused, e.g., suppositories, ointments, creams, gels, solutions and thelike, which will be described in detail below. Also, one or moreadditional types of drugs, i.e., pharmacologically active agents otherthan vasoactive agents, may be incorporated into the pharmaceuticalformulations. In other aspects of the invention, vaginal administrationof a vasoactive agent as just described is used to prevent theoccurrence of yeast infections, to improve vaginal muscle tone andtissue health, to enhance vaginal lubrication, or to minimize collagenmisdeposition resulting from hypoxia as well as the associated lack ofelasticity resulting from the collagen misdeposition.

In another aspect of the invention, pharmaceutical formulations areprovided for carrying out the aforementioned methods. The formulationscontain a vasoactive agent as described above, a pharmaceuticallyacceptable vehicle, and, optionally, one or more additionalpharmacologically active agents.

In still another aspect of the invention, a drug delivery device isprovided for administering a pharmaceutical formulation directly to theclitoral area. The device includes a drug reservoir comprising avasoactive agent in a pharmaceutical formulation, as provided herein,and a clitoral applicator.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 is a pictorial representation of a clitoral drug applicationdevice that can be used as a carrier and dispenser for pharmaceuticalcompositions.

FIG. 2 is an exploded view of one embodiment of a transurethraltherapeutic device which may be used in conjunction with the presentmethod.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

Before describing the present invention in detail it is to be understoodthat this invention is not limited to delivery of specific drugs,carriers or use of particular drug delivery systems, as such may vary.It is also to be understood that the terminology used herein is for thepurpose of describing particular embodiments only, and is not intendedto be limiting.

It must be noted that, as used in this specification and the appendedclaims, the singular forms “a,” “an” and “the” include plural referentsunless the context clearly dictates otherwise. Thus, for example,reference to “a vasoactive agent” includes a mixture of two or morevasoactive agents, reference to “a pharmaceutically acceptableexcipient” includes mixtures of such excipients, and the like.

In describing and claiming the present invention, the followingterminology will be used in accordance with the definitions set outbelow.

The terms “active agent,” “drug” and “pharmacologically active agent”are used interchangeably herein to refer to a chemical material orcompound which, when administered to an organism (human or animal)induces a desired pharmacologic and/or physiologic effect by localand/or systemic action. The pharmacologically active agents used inconjunction with the present invention are vasoactive agents.

The term “vaginal delivery” is used herein to mean direct administrationof a pharmaceutical composition to the vagina of the individualundergoing treatment. Generally, “vaginal delivery” of a pharmaceuticalcomposition involves administration to the distal several centimeters ofthe vagina.

The term “vulvar delivery” or “vulvar administration” is used herein torefer to application of a pharmaceutical formulation to the vulvar areaof an individual undergoing treatment. The term is intended to encompassapplication to the clitoris as well as the surrounding vulvar area. Theterms “vulvar delivery” and “clitoral delivery” are used interchangeablyherein and are both intended to refer to administration to the vulvararea of the individual undergoing treatment.

The term “urethral delivery” (sometimes referred to as “intraurethral”or “transurethral” delivery) is used herein to mean directadministration of a pharmaceutical composition to the urethra of theindividual undergoing treatment. Generally, “urethral” delivery of apharmaceutical composition involves administration to the distal portionof the urethra.

“Carriers” or “vehicles” as used herein refer to carrier materialssuitable for vaginal, vulvar and/or urethral drug administration, andinclude any such materials known in the art, e.g., any liquid, gel,solvent, liquid diluent, solubilizer, or the like, which is nontoxic andwhich does not interact with other components present in thepharmaceutical formulation or drug delivery system in a deleteriousmanner.

By an “effective” amount of a drug or pharmacologically active agent ismeant a nontoxic but sufficient amount of the drug or agent to providethe desired effect. For example, in treating sexual dysfunction inwomen, an “effective” amount of drug would be an amount that is at leastsufficient to provide the desired degree of treatment. Similarly, inpreventing yeast infections, an “effective” amount of drug would be anamount that is at least sufficient to prevent a vaginal yeast infectionin a female individual.

In a first embodiment, the invention relates to a method for treatingsexual dysfunction in a female individual and involves vaginal, vulvarand/or urethral administration of a pharmaceutical formulationcontaining a vasoactive agent, preferably a vasodilator. Preferredvasodilators are selected from the group consisting of naturallyoccurring prostaglandins, synthetic prostaglandin derivatives,endothelial-derived relaxation factors, vasoactive intestinalpolypeptide agonists, smooth muscle relaxants, leukotriene inhibitors,pharmaceutically acceptable salts, esters, analogs, derivatives,prodrugs, and inclusion complexes thereof, and combinations of any ofthe foregoing, in combination with a pharmaceutically acceptablevehicle.

Particularly preferred vasodilating agents are naturally occurringprostaglandins or hydrolyzable lower alkyl esters of a naturallyoccurring prostaglandin, as well as synthetic or semisyntheticprostaglandins.

The “naturally occurring” prostaglandins useful in conjunction with thepresent invention are PGE₀, PGE₁, PGA₁, PGB₁, PGF_(1α), 19-hydroxy-PGA₁,19-hydroxy-PGB₁, PGE₂, PGA₂, PGB₂, 19-hydroxy-PGA₂, 19-hydroxy-PGB₂,PGE₃, PGF_(3α)and PGI₂, with PGE₀, PGE₁ and PGE₂ particularly preferred.The term “synthetic prostaglandin derivatives” is intended to encompassknown or unknown compounds related to the aforementioned naturallyoccurring prostaglandins that are chemically synthesized using startingmaterials other than one of the naturally occurring prostaglandins. Theterm “semisynthetic prostaglandin derivatives” refers to known orunknown compounds related to the aforementioned naturally occurringprostaglandins and that are synthesized therefrom. Synthetic andsemisynthetic prostaglandins include, but are not limited to, carboprosttromethamine, dinoprost tromethamine, dinoprostone, lipoprost,gemeprost, metenoprost, sulprostone and tiaprost.

Additional vasoactive agents useful in conjunction with the presentinvention include endothelial-derived relaxation factors (“EDRFs”) suchas nitric oxide releasing agents, e.g., sodium nitroprusside anddiazenium diolates, or “NONOates.” NONOates include, but are not limitedto,(Z)-1-{N-methyl-N-[6-(N-methyl-ammoniohexyl)amino]}diazen-1-ium-1,2-diolate(“MAHMA/NO”),(Z)-1-[N-(3-ammoniopropyl)-N-(n-propyl)amino]diazen-1-ium-1,2-diolate(“PAPA/NO”),(Z)-1-{N-[3-aminopropyl]-N-[4-(3-aminopropylammonio)butyl]amino}diazen-1-ium-1,2-diolate(spermine NONOate or “SPER/NO”) and sodium(Z)-1-(N,N-diethylamino)-diazen-1-ium-1,2-diolate (diethylamine NONOateor “DEA/NO”) and derivatives thereof). Still other vasoactive agentsinclude vasoactive intestinal polypeptide agonists and derivativesthereof (particularly derivatives in the form of hydrolyzable loweralkyl esters), smooth muscle relaxants, leukotriene inhibitors, calciumchannel blockers, β2-adrenergic agonists, angiotensin-converting enzyme(“ACE”) inhibitors, and angiotensin II receptor antagonists, andphosphodiesterase inhibitors.

Suitable phosphodiesterase inhibitors include, but are not limited to,inhibitors of the type III phosphodiesterases (cAMP-specific-cGMPinhibitable form), the type IV phosphodiesterases (high affinity-highspecificity cAMP form) and the type V phosphodiesterases (the cGMPspecific form). Examples of type III phosphodiesterase inhibitorsinclude, but are not limited to, bypyridines such as milrinone andamrinone, imidazolones such as piroximone and enoximone,dihydropyridazinones such as imazodan, 5-methylimazodan, indolidan andICI118233, quinolinone compounds such as cilostamide, cilostazol andvesnarinone, and other compounds such as bemoradan, anergrelide,siguazodan, trequensin, pimobendan, SKF-94120, SKF-95654, lixazinone andisomazole. Examples of type IV phosphodiesterase inhibitors include, butare not limited to, rolipram and rolipram derivatives such as RO20-1724,nitraquazone and nitraquazone derivatives such as CP-77059 andRS-25344-00, xanthine derivatives such as denbufylline and ICI63197, andmiscellaneous other compounds such as EMD54622, LAS-31025 and etazolate.Examples of type V phosphodiesterase inhibitors include, but are notlimited to, zaprinast, MY5445, dipyridamole, and sildenafil. Othersuitable type V phosphodiesterase inhibitors are disclosed in PCTPublication Nos. WO 94/28902 and WO 96/16644.

The compounds described in PCT Publication No. WO 94/28902 arepyrazolopyrimidinones. Examples of the inhibitor compounds include5-(2-ethoxy-5-morpholinoacetyl-phenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,5-(5-morpholino-acetyl-2-n-propoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,5-[2-ethoxy-5-(4-methyl-1-piperazinylsulfonyl)-phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,5-[2-allyloxy-5-(4-methyl-1-piperazinylsulfonyl)-phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,5-[2-ethoxy-5-[4-(2-propyl)-1-piperazinylsulfonyl)-phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,5-[2-ethoxy-5-[4-(2-hydroxyethyl)-1-piperazinylsulfonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,5-[5-[4-(2-hydroxyethyl)-1-piperazinylsulfonyl]-2-n-propoxyphenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,5-[2-ethoxy-5-(4-methyl-1-piperazinylcarbonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,and5-[2-ethoxy-5-(1-methyl-2-imidazolyl)phenyl]-1-methyl3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one.

The phosphodiesterase inhibitors described in PCT Publication No. WO96/16644 include griseolic acid derivatives, 2-phenylpurinonederivatives, phenylpyridone derivatives, fused and condensedpyrimidines, pyrimidopyrimidine derivatives, purine compounds,quinazoline compounds, phenylpyrimidone derivative, imidazoquinoxalinonederivatives or aza analogues thereof, phenylpyridone derivatives, andothers. Specific examples of the phosphodiesterase inhibitors disclosedin WO 96/16644 include1,3-dimethyl-5-benzylpyrazolo[4,3-d]pyrimidine-7-one,2-(2-propoxyphenyl)-6-purinone,6-(2-propoxyphenyl)-1,2-dihydro-2-oxypyridine-3-carboxamide,2-(2-propoxyphenyl)-pyrido[2,3-d]pyrimid-4(3H)-one,7-methylthio-4-oxo-2-(2-propoxyphenyl)-3,4-dihydro-pyrimido[4,5-d]pyrimidine,6-hydroxy-2-(2-propoxyphenyl)-pyrimidine-4-carboxamide,1-ethyl-3-methylimidazo[1,5a]quinoxalin-4(5H)-one,4-phenyl-methylamino-6-chloro-2-(1-imidazoloyl)quinazoline,5-ethyl-8-[3-(N-cyclohexyl-N-methyl-carbamoyl)-propyloxy]4,5-dihydro-4-oxo-pyrido[3,2-e]-pyrrolo[1,2-a]pyrazine,5′-methyl-3′-(phenylmethyl)-spiro[cyclopentane-1,7′(8′H)-(3′H)-imidazo[2,1-b]purin]4′(5′H)-one,1-[6-chloro-4-(3,4-methylenedioxybenzyl)-aminoquinazolin-2-yl)piperidine-4-carboxylicacid, (6R,9S)-2-(4-trifluoromethyl-phenyl)methyl-5-methyl-3,4,5,6a,7,8,9,9a-octahydrocyclopent[4,5]-imidazo[2,1b]-purin-4-one,1-t-butyl-3-phenylmethyl-6-(4-pyridyl)pyrazolo[3,4-d]-pyrimid-4-one,1-cyclopentyl-3-methyl-6-(4-pyridyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimid-4-one,2-butyl-1-(2-chlorobenzyl)6-ethoxy-carbonylbenzimidaole, and2-(4-carboxypiperidino)-4-(3,4-methylenedioxybenzyl)amino-6-nitroquinazoline,and 2-phenyl-8-ethoxycycloheptimidazole.

Still other type V phosphodiesterase inhibitors useful in conjunctionwith the present invention include: IC-351 (ICOS);4-bromo-5-(pyridylmethylamino)-6-[3-(4-chlorophenyl)-propoxy]-3(2H)pyridazinone;1-[4-[(1,3-benzodioxol-5-ylmethyl)amino]-6-chloro-2-quinazolinyl]4-piperidine-carboxylicacid, monosodium salt;(+)-cis-5,6a,7,9,9,9a-hexahydro-2-[4-(trifluoromethyl)-phenylmethyl-5-methyl-cyclopent-4,5]imidazo[2,1-b]purin4(3H)one;furazlocillin;cis-2-hexyl-5-methyl-3,4,5,6a,7,8,9,9a-octahydrocyclopent[4,5]imidazo[2,1-b]purin-4-one;3-acetyl-1-(2-chlorobenzyl)-2-propylindole-6-carboxylate;4-bromo-5-(3-pyridylmethylamino)-6-(3-(4-chlorophenyl)propoxy)-3-(2H)pyridazinone;1-methyl-5-(5-morpholinoacetyl-2-n-propoxyphenyl)-3-n-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one;1-[4-[(1,3-benzodioxol-5-ylmethyl)amino]-6-chloro-2-quinazolinyl]-4-piperidinecarboxylicacid, monosodium salt; Pharmaprojects No. 4516 (Glaxo Wellcome);Pharmaprojects No. 5051 (Bayer); Pharmaprojects No. 5064 (Kyowa Hakko;see WO 96/26940); Pharmaprojects No. 5069 (Schering Plough); GF-196960(Glaxo Wellcome); and Sch-51866.

Other phosphodiesterase inhibitors that may be used in the method ofthis invention include nonspecific phosphodiesterase inhibitors such astheophylline, IBMX, pentoxifylline and papaverine, and directvasodilators such as hydralazine.

Other suitable vasoactive agents include, but are not limited to:nitrates and like compounds such as nitroglycerin, isosorbide dinitrate,erythrityl tetranitrate, amyl nitrate, molsidomine, linsidominechlorhydrate (“SIN-1”), S-nitroso-N-acetyl-d,1-penicillamine (“SNAP”)and S-nitroso-N-glutathione (“SNO-GLU”); long and short actingα-blockers such as phenoxybenzamine, dibenamine, doxazosin, terazosin,phentolamine, tolazoline, prazosin, trimazosin, alfuzosin, tamsulosinand indoramin; ergot alkaloids such as ergotamine and ergotamineanalogs, e.g., acetergamine, brazergoline, bromerguride, cianergoline,delorgotrile, disulergine, ergonovine maleate, ergotamine tartrate,etisulergine, lergotrile, lysergide, mesulergine, metergoline,metergotamine, nicergoline, pergolide, propisergide, proterguride andterguride; antihypertensive agents such as diazoxide, hydralazine andminoxidil; nimodepine; pinacidil; cyclandelate; dipyridamole;isoxsuprine; chlorpromazine; haloperidol; yohimbine; and trazodone.

The pharmaceutical formulations of the invention include a vasoactiveagent as just described, or a pharmaceutically acceptable salt, ester,analog, derivative, prodrug or inclusion complex thereof. Additionally,simultaneous administration of two or more vasoactive agents may bedesirable and may in some cases exhibit a synergistic effect. Thecombination of prazosin with prostaglandin E₁ has been found to beparticularly advantageous in this regard; the latter drug appears to acta permeation enhancer for prazosin, i.e., it appears to increase therate at which prazosin permeates through the skin or mucosal tissue andenters the bloodstream.

“Pharmaceutically acceptable” salts, esters, analogs, derivatives,prodrugs or inclusion complexes refer to those salts, esters, analogs,derivatives, prodrugs and inclusion complexes that retain the biologicaleffectiveness and properties of the base compounds and are notbiologically or otherwise undesirable.

Salts, esters, analogs, derivatives, prodrugs and inclusion complexes ofthe active agents may be prepared using standard procedures known tothose skilled in the art of synthetic organic chemistry and described,for example, by J. March, Advanced Organic Chemistry: Reactions,Mechanisms and Structure, 4th Ed. (New York: Wiley-Interscience, 1992).For example, acid addition salts are prepared from the free base(typically wherein the neutral form of the drug has a neutral —NH₂group) using conventional means, involving reaction with a suitableacid. Generally, the base form of the drug is dissolved in a polarorganic solvent such as methanol or ethanol and the acid is addedthereto. The resulting salt either precipitates or may be brought out ofsolution by addition of a less polar solvent. Suitable acids forpreparing acid addition salts include both organic acids, e.g., aceticacid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malicacid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaricacid, citric acid, benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,salicylic acid, and the like, as well as inorganic acids, e.g.,hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like. An acid addition salt may be reconvertedto the free base by treatment with a suitable base. Conversely,preparation of basic salts of acid moieties that may be present on adrug are prepared in a similar manner using a pharmaceuticallyacceptable base such as sodium hydroxide, potassium hydroxide, ammoniumhydroxide, calcium hydroxide, trimethylamine, or the like. For example,basic salts may be prepared from prostaglandins existing in acid form,i.e., prostaglandins retaining the prostanoic acid functionality,Preparation of esters involves functionalization of hydroxyl and/orcarboxyl groups that may be present within the molecular structure ofthe drug. The esters are typically acyl-substituted derivatives of freealcohol groups, i.e., moieties that are derived from carboxylic acids ofthe formula RCOOH where R is alkyl, and preferably is lower alkyl.Esters can be reconverted to the free acids, if desired, by usingconventional hydrogenolysis or hydrolysis procedures. Inclusioncomplexes are complexes formed by interaction of macrocyclic compoundscontaining an intramolecular cavity of molecular dimensions with thesmaller, pharmacologically active agent. Preferred inclusion complexesare formed from α-, β- and γ-cyclodextrins, or from clathrates, in whichthe “host” molecules form a crystal lattice containing spaces in which“guest” molecules (i.e., in this case, the vasoactive agent) will fit.See, e.g., Hagan, Clathrate Inclusion Compounds (New York: Reinhold,1962). Inclusion complexes for use in conjunction with the method of thepresent invention can be prepared using methods known in the art,typically by admixing a macrocyclic compound such as a cyclodextrin withthe active agent, under conditions that result in the incorporation ofthe active agent into the intramolecular cavity of the host molecule.

The pharmaceutical formulations used in the methods of the presentinvention may also include one or more pharmacologically active agentsother than the vasoactive agent. For example, the formulations maycontain a steroid or a steroid agonist, partial agonist, or antagonist.

Steroids will generally be selected from the group consisting ofprogestins, estrogens, and combinations thereof. Suitable progestinsinclude, but are not limited to, acetoxy-pregnenolone, allylestrenol,anagestone acetate, chlormadinone acetate, cyproterone, cyproteroneacetate, desogestrel, dihydrogesterone, dimethisterone, ethisterone(17α-ethynyltestosterone), ethynodiol diacetate, flurogestone acetate,gestadene, hydroxyprogesterone, hydroxyprogesterone acetate,hydroxyprogesterone caproate, hydroxymethylprogesterone,hydroxymethylprogesterone acetate, 3-ketodesogestrel, levonorgestrel,lynestrenol, medrogestone, medroxyprogesterone acetate, megestrol,megestrol acetate, melengestrol acetate, norethindrone, norethindroneacetate, norethisterone, norethisterone acetate, norethynodrel,norgestimate, norgestrel, norgestrienone, normethisterone, andprogesterone. Progesterone, cyproterone acetate, norethindrone,norethindrone acetate and levonorgestrel are preferred progestins.Suitable estrogens include synthetic and natural estrogens such as:estradiol (i.e., 1,3,5-estratriene-3,17β-diol, or “β-estradiol”) and itsesters, including estradiol benzoate, valerate, cypionate, heptanoate,decanoate, acetate and diacetate; 17α-estradiol; ethynylestradiol (i.e.,17α-ethynylestradiol) and esters and ethers thereof, includingethynylestradiol 3-acetate and ethynylestradiol 3-benzoate; estriol andestriol succinate; polyestrol phosphate; estrone and its esters andderivatives, including estrone acetate, estrone sulfate, and piperazineestrone sulfate; quinestrol; mestranol; and conjugated equine estrogens.Estradiol and ethynylestradiol are particularly preferred.

Additionally, particularly for vulvar administration, it may bedesirable to include an androgenic agent in the formulation. Suitableandrogenic agents include, but are not limited to: the naturallyoccurring androgens and derivatives thereof, including androsterone,androsterone acetate, androsterone propionate, androsterone benzoate,androstenediol, androstenediol-3-acetate, androstenediol-17-acetate,androstenediol-3,17-diacetate, androstenediol-17-benzoate,androstenediol-3-acetate-17-benzoate, androstenedione, ethylestrenol,oxandrolone, nandrolone phenpropionate, nandrolone decanoate, nandrolonefurylpropionate, nandrolone cyclohexane-propionate, nandrolone benzoate,nandrolone cyclohexanecarboxylate, stanozolol, dromostanolone,dromostanolone propionate, testosterone, dehydroepiandrosterone (DHEA;also termed “prasterone”), sodium dehydroepiandrosterone sulfate,4-dihydrotestosterone (DHT; also termed “stanolone”), and5α-dihydrotestosterone; pharmaceutically acceptable esters oftestosterone and 4-dihydrotestosterone, typically esters formed from thehydroxyl group present at the C-17 position, including, but not limitedto, the enanthate, propionate, cypionate, phenylacetate, acetate,isobutyrate, buciclate, heptanoate, decanoate, undecanoate, caprate andisocaprate esters; and pharmaceutically acceptable derivatives oftestosterone such as methyl testosterone, testolactone, oxymetholone andfluoxymesterone. Testosterone and testosterone esters, such astestosterone enanthate, testosterone propionate and testosteronecypionate, are particularly preferred.

Examples of preferred steroid antagonists or partial agonists aretamoxifen, cenchroman, clomiphene, droloxifene, raloxifene andpharmaceutically acceptable salts thereof, particularly tamoxifen orclomiphene citrate.

It may in some cases be desirable or necessary to include a detergent inthe formulation, in an amount effective to increase solubility of thevasoactive agent in the vehicle and bioavailability of the agentfollowing administration. The detergent will typically be a nonionic,anionic, cationic or amphoteric surfactant. In the practice of theinvention, the surfactant is selected such that local irritation at thesite of administration is avoided. Examples of suitable surfactantsinclude Tergitol® and Triton® surfactants (Union Carbide Chemicals andPlastics, Danbury, Conn.), polyoxyethylenesorbitans, e.g., TWEEN®surfactants (Atlas Chemical Industries, Wilmington, Del.), andpharmaceutically acceptable fatty acid esters such as lauryl sulfate andthe like.

The formulations may also include a chemical compound to enhancepermeation of the vasoactive agent through the mucosal tissue orurethral membrane, i.e., a “permeation enhancer.” Suitable permeationenhancers include those generally useful in conjunction with topical,transdermal or transmucosal drug delivery. Examples of suitablepermeation enhancers include dimethylsulfoxide (“DMSO”), dimethylformamide (“DMF”), N,N-dimethylacetamide (“DMA”), decylmethylsulfoxide(“C₁₀MSO”), polyethylene glycol monolaurate (“PEGML”), glycerolmonolaurate, lecithin, the 1-substituted azacycloheptan-2-ones,particularly 1-n-dodecylcyclazacycloheptan-2-one (available under thetrademark Azone® from Nelson Research & Development Co., Irvine,Calif.), lower alkanols (e.g., ethanol), SEPA® (available from MacrochemCo., Lexington, Mass.), and surfactants as discussed above, including,for example, Tergitol®, Nonoxynol-9® and TWEEN-80®.

The pharmaceutical formulations used herein typically contain one ormore pharmaceutically acceptable carriers (also termed “excipients” or“vehicles”) suited to the particular type of formulation, i.e., gel,ointment, suppository, or the like. The vehicles are comprised ofmaterials of naturally occurring or synthetic origin that do notadversely affect the vasoactive agent or other components of theformulation. Suitable carriers for use herein include water, silicone,waxes, petroleum jelly, polyethylene glycol, propylene glycol,liposomes, sugars such as mannitol and lactose, and a variety of othermaterials, depending, again, on the specific type of formulation used.

In some cases, the formulations used in the present methods include anenzyme inhibitor, i.e., a compound effective to inhibit enzymes presentin the vagina, vulvar area or urethra that could degrade or metabolizethe pharmacologically active agent. For example, with a prostaglandin asthe active agent, it may be preferred to include an effective inhibitingamount of a compound effective to inhibit prostaglandin-degradingenzymes. Such compounds will include, for example, fatty acids, fattyacid esters, and NAD inhibitors. These formulations are believed to benovel.

The compositions used herein may be in the form of an ointment, cream,emulsion, lotion, gel, solid, solution, suspension, foam or liposomalcomposition; such formulations may be used for clitoral, vulvar orvaginal delivery. Alternatively, the compositions may be containedwithin a vaginal ring, tampon, suppository, sponge, pillow, puff, orosmotic pump system; these platforms are useful solely for vaginaldelivery. Preferred formulations for urethral delivery are ointments,emulsions, suppositories, liposomal compositions, powders, and the like.Preferred formulations are long-acting or pulsatile release solid phasesystems, as well as ointments, gels and suppositories. Methods forpreparing various dosage forms are known, or will be apparent, to thoseskilled in this art; for example, see Remington's PharmaceuticalSciences, 18th Ed. (Easton, Pa.: Mack Publishing Company, 1990).

Ointments are semisolid preparations that are typically based onpetrolatum or other petroleum derivatives. The specific ointment base tobe used, as will be appreciated by those skilled in the art, is one thatwill provide for optimum drug delivery. As with other carriers orvehicles, an ointment base should be inert, stable, nonirritating andnonsensitizing. As explained in Remington: The Science and Practice ofPharmacy, Supra, at pages 1399-1404, ointment bases may be grouped infour classes: oleaginous bases; emulsifiable bases; emulsion bases; andwater-soluble bases. Oleaginous ointment bases include, for example,vegetable oils, fats obtained from animals, and semisolid hydrocarbonsobtained from petroleum. Emulsifiable ointment bases, also known asabsorbent ointment bases, contain little or no water and include, forexample, hydroxystearin sulfate, anhydrous lanolin and hydrophilicpetrolatum. Emulsion ointment bases are either water-in-oil (W/O)emulsions or oil-in-water (O/W) emulsions, and include, for example,cetyl alcohol, glyceryl monostearate, lanolin and stearic acid.Preferred water-soluble ointment bases are prepared from polyethyleneglycols of varying molecular weight; again, reference may be had toRemington: The Science and Practice of Pharmacy for further information.

Lotions are preparations that may be applied without friction, and aretypically liquid or semiliquid preparations in which solid particles,including the active agent, are present in a water or alcohol base.Lotions are usually suspensions of solids, and preferably, for thepresent purpose, comprise a liquid oily emulsion of the oil-in-watertype. It is generally necessary that the insoluble matter in a lotion befinely divided. Lotions will typically contain suspending agents toproduce better dispersions as well as compounds useful for localizingthe active agent in contact with the skin, e.g., methylcellulose, sodiumcarboxymethylcellulose, or the like.

Pharmaceutical emulsion formulations are generally formed from adispersed phase (e.g., a pharmacologically active agent), a dispersionmedium and an emulsifying agent. If desired, emulsion stabilizers can beincluded in the formulation as well. A number of pharmaceutically usefulemulsions are known in the art, including oil-in-water (o/w)formulations, water-in-oil (w/o) formulations and multiple emulsionssuch as w/o/w or o/w/o formulations. Emulsifying agents suitable for usein such formulations include, but are not limited to, TWEEN 60®, Span80®, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate andsodium lauryl sulfate.

Pharmaceutical creams, are, as known in the art, viscous liquid orsemisolid emulsions, either oil-in-water or water-in-oil. Cream basesare water-washable, and contain an oil phase, an emulsifier and anaqueous phase. The oil phase, also sometimes called the “internal”phase, is generally comprised of petrolatum and a fatty alcohol such ascetyl or stearyl alcohol; the aqueous phase usually, although notnecessarily, exceeds the oil phase in volume, and generally contains ahumectant. The emulsifier in a cream formulation is generally anonionic, anionic, cationic or amphoteric surfactant.

The above pharmaceutical formulations are formed by dispersing thefinely divided or dissolved vasoactive agent uniformly throughout thevehicle or base using conventional techniques, typically by a levigatingthe agent with a small quantity of the base to form a concentrate, whichis then diluted geometrically with further base. Alternatively, amechanical mixer may be used. Creams, lotions and emulsions are formedby way of a two-phase heat system, wherein oil-phase ingredients arecombined under heat to provide a liquified, uniform system. Theaqueous-phase ingredients are separately combined using heat. The oiland aqueous phases are then added together with constant agitation andallowed to cool. At this point, concentrated agents may be added as aslurry. Volatile or aromatic materials can be added after the emulsionhas sufficiently cooled. Preparation of such pharmaceutical compositionsis within the general skill of the art.

The vasoactive agent can also be incorporated into a gel formulationusing known techniques. Two-phase gel systems generally comprise asuspension or network of small, discrete particles interpenetrated by aliquid to provide a dispersed phase and a liquid phase. Single-phase gelsystems are formed by distributing organic macromolecules uniformlythroughout a liquid such that there are no apparent boundaries betweenthe dispersed and liquid phases. Suitable gelling agents for use hereininclude synthetic macromolecules (e.g., Carbomers®, polyvinyl alcoholsand polyoxyethylene-polyoxypropylene copolymers), gums such astragacanth, as well as sodium alginate, gelatin, methylcellulose, sodiumcarboxymethylcellulose, methylhydroxyethyl cellulose and hydroxyethylcellulose. In order to prepare a uniform gel, dispersing agents such asalcohol or glycerin can be added, or the gelling agent can be dispersedby trituration, mechanical mixing or stirring, or combinations thereof.

Liposomes are microscopic vesicles having a lipid wall comprising alipid bilayer, and can be used as drug delivery systems herein as well.Generally, liposome formulations are preferred for poorly soluble orinsoluble pharmaceutical agents. Liposomal preparations for use in theinstant invention include cationic (positively charged), anionic(negatively charged) and neutral preparations. Cationic liposomes arereadily available. For example,N[1-2,3-dioleyloxy)propyl]-N,N,N-triethylammonium (“DOTMA”) liposomesare available under the tradename Lipofectin® (GIBCO BRL, Grand Island,N.Y.). Similarly, anionic and neutral liposomes are readily available aswell, e.g., from Avanti Polar Lipids (Birmingham, Ala.), or can beeasily prepared using readily available materials. Such materialsinclude phosphatidyl choline, cholesterol, phosphatidyl ethanolamine,dioleoylphosphatidyl choline (“DOPC”), dioleoylphosphatidyl glycerol(“DOPG”), dioleoylphoshatidyl ethanolamine (“DOPE”), among others. Thesematerials can also be mixed with DOTMA in appropriate ratios. Methodsfor making liposomes using these materials are well known in the art.

The pharmaceutical formulations of the invention are typically containedwithin drug delivery systems that provide a specific, predeterminedagent release profile, e.g., pulsatile, continuous, cyclical or diurnal.Such systems can include, for example, osmotic pumps that are capable ofdelivering variable amounts of the agent in a pulsatile manner. Osmoticpump systems typically involve incorporation of the pharmaceutical agentwithin a hard coating shell that is usually semi-permeable, e.g., amicroporous cellulose acetate latex coating; the shell further containsa bore hole drilled into the outer layer. After delivery, water from thesurrounding moist environment is osmotically pulled into shell throughthe bore hole, dissolving the agent and creating a high integralpressure sufficient to effect release of the agent from the shell. Inthis manner, the active agent is automatically “pulsed” out of thedelivery system. A number of suitable osmotic pumps have been describedin the art. See, for example, Appel et al. (1992) Pharm. Res.2:1664-1667 and Keinbloesem et al. (1984) Clin. Pharm. Therapeut.36:396-401.

Other drug delivery platforms capable of providing a pulsatile,continuous, cyclical or diurnal agent release profile include thoseformed from bio-erodible polymers, wherein the vasoactive agent isdispersed within a polymer matrix. Such polymers are selected such thatthey bioerode in the presence of moisture, and provide for sustainedagent release at readily predictable rates.

More particularly, release of the vasoactive agent can be controlled bydissolution (bioerosion) of a polymer using either encapsulateddissolution control or matrix dissolution control. In encapsulateddissolution control, the vasoactive agent is coated with a membrane ofslowly dissolving polymeric or wax materials. When the encapsulatingmembrane has dissolved, the agent core is available for immediaterelease and adsorption across the epithelial or mucosal surfaces of thevagina or vulvar area. Bioerodible coating materials may be selectedfrom a variety of natural and synthetic polymers, depending on the agentto be coated and the desired release characteristics. Exemplary coatingmaterials include gelatins, carnauba wax, shellacs, ethylcellulose,cellulose acetate phthalate or cellulose acetate butyrate. Release ofthe agent is controlled by adjusting the thickness and dissolution rateof the polymeric membrane. A uniform sustained release formulation canbe attained by compressing a population of particles of the agent withvarying membrane thickness (e.g., varying erosion-times) into a tabletform for a single administration.

In matrix dissolution control, the vasoactive agent is dissolved ordispersed within a matrix of, for example, an erodible wax. The agent isreleased for adsorption across the epithelial or mucosal surfaces of thevagina or vulvar area as the matrix bioerodes. The rate of agentavailability is generally controlled by the rate of penetration of thedissolution media (i.e., vaginal fluids) into the matrix, wherein therate of penetration is dependent on the porosity of the matrix material.Bioerodible matrix dissolution delivery systems can be prepared bycompressing the vasoactive agent with a slowly soluble polymer carrierinto a tablet or suppository form. There are several methods ofpreparing drug/wax particles including congealing and aqueous dispersiontechniques. In congealing methods, the vasoactive agent is combined witha wax material and either spray-congealed, or congealed and thenscreened. For an aqueous dispersion, the vasoactive agent/waxcombination is sprayed or placed in water and the resulting particlescollected. Matrix dosage formulations can be formed by compaction orcompression of a mixture of vasoactive agent, polymer and excipients.

In an alternative embodiment, the pharmaceutical formulation isadministered in the form of biodegradable adhesive film or sheet thatadheres to the vulvar area. Such drug delivery systems are generallycomposed of a biodegradable adhesive polymer based on a polyurethane, apoly(lactic acid), a poly(glycolic acid), a poly(ortho ester), apolyanhydride, a polyphosphazene, or a mixture or copolymer thereof.Preferred biodegradable adhesive polymers include polyurethanes andblock copolyurethanes containing peptide linkages, simple mixtures ofpolyurethanes and polylactides, and copolymers of acrylates and mono- ordisaccharide residues.

If desired, a clitoral application device may be used to facilitateapplication of a pharmaceutical formulation containing a vasoactiveagent directly to the clitoral area. Referring to FIG. 1, an embodimentof a clitoral application device is generally indicated at 2. The device2 is configured in the shape of an elongate patch having a top surface4. The patch can be formed from any suitably flexible material such aspolymers or fibrous materials. The patch is dimensioned to be generallyco-extensive with the external female genitalia. The top surface 4 ofthe patch has an upper region 6 and a lower region 8 that correspond tothe upper and lower portions of the female genitalia. A clitoralapplicator, generally shown at 10, is provided on the top surface 4 ofthe patch at the upper region 6 thereof. The clitoral applicator 10generally comprises an extended finger or protuberance 12 that isdisposed over a reservoir 14 containing the pharmaceutical formulation.The reservoir 14 can be formed by disposing the pharmaceutical betweenthe top surface 4 of the patch and a permeable membrane 16 thatencircles the base of the protuberance 12. An optional suction tip 18can be provided at the distal end of the protuberance 12 to facilitatepositioning of the device.

The membrane 16 contains micropores through which the pharmaceuticalagent can diffusively migrate to contact the clitoral wall. A number ofsuitable porous materials are known, such as water insoluble naturalgums, cellulose, cellulose diacetate, microporous polyurethanes,polyarylenes, polycarbonates, polysulfones and polyamides, ormicroporous copolymers of polyvinylchloride and acrylonitrile. Therelease rate of the vasoactive agent can be readily controlled byadjusting the pore size in the membrane, the physical attributes of thepharmaceutical formulation (e.g., providing colloidal pharmaceuticalsolutions, suspensions or sols and/or adjusting the ratio of the size ofthe pores to the molecular size of the pharmaceutical agent), or byadjusting the thickness of the membrane. In addition, controlled orsustained release pharmaceutical formulations can be used in theapplication device 2 to provide a desired release effect.

In use, the device 2 is positioned by inserting the protuberance 12 toextend into the clitoral hood. The device can then be left in place fora suitable time to administer the vasoactive agent with the lower region8 extending over the remainder of the genitalia. If desired, an opening20 can be provided to allow for urethral voiding during drugadministration. If the device includes a suction tip 18, a vacuum can beformed against the surface of the clitoral glans by pressing theprotuberance firmly into place within the clitoris.

Transurethral administration of the present formulations can be carriedout in a number of different ways. For example, the drug can beintroduced into the urethra from a flexible tube, squeeze bottle, pumpor aerosol spray. The drug may also be contained in coatings, pellets orsuppositories which are absorbed, melted or bioeroded in the urethra.The drug formulation may be included as a coating on the exteriorsurface of a urethral insert. A preferred drug delivery device foradministering a drug transurethrally is shown in FIG. 2.

In FIG. 2, a transurethral drug delivery device is shown generally at22. The device comprises a transurethral inserter 24 having an easilygraspable segment 26 that has opposing symmetrically concave surfaces 28and 30 adapted to be held by two fingers. Drug is contained within shaft32, which is sized to fit within the urethra. A longitudinal plunger,the tip of which is seen at 34, is slidably insertable into thelongitudinal bore contained within shaft 32. To extrude drug into theurethra, shaft 32 is inserted into the urethra, and plunger tip 34 ispushed into segment 26. The inserter 24 is then removed. Prior to use,and during storage, the device is capped with elongate cap 36 which fitssnugly over flange 38 at the proximal end of shaft 32. The cap 36 isprovided with a series of parallel ridges 40 to facilitate gripping ofthe cap and removal from inserter 24.

Although the configuration shown in FIG. 2 is a preferred configuration,other inserter/container configurations and mechanisms can be used,providing that a predetermined quantity of drug can be introduced fromthe inserter at a predetermined depth in the urethra.

For treatment of sexual dysfunction, the pharmaceutical formulation isadministered either vaginally, to the vulvar area, and/or to theurethra. The amount of active agent administered is at least the minimumnecessary to treat the dysfunction, e.g., excitement stage dysfunctionssuch as touch sensation impairment, loss of clitoral sensation, vaginaldryness, urinary incontinence and concomitant dyspareunia. In thetreatment of dyspareunia, prostaglandin E₁, E₂, and analogues thereofcan be administered at a level sufficient to exceed naturally occurringlevels at the point of administration, for example in an amount rangingfrom 50 to 500 μg/kg.

In addition to treatment of sexual dysfunction, the formulations of theinvention have other uses as well. They may be administered vaginally toprevent the occurrence of yeast infections, to improve vaginal muscletone and tissue health, to enhance vaginal lubrication, and to minimizecollagen misdeposition associated with hypoxia.

It is to be understood that while the invention has been described inconjunction with the preferred specific embodiments thereof, that theforegoing description as well as the examples that follow are intendedto illustrate and not limit the scope of the invention. Other aspects,advantages and modifications within the scope of the invention will beapparent to those skilled in the art to which the invention pertains.

All patents, patent applications, patent publications and non-patentliterature references mentioned herein are incorporated by reference intheir entireties.

EXAMPLE 1

A cream formulation is prepared using a synthetic or semisyntheticprostaglandin. The cream includes the following components:

Prostaglandin 0.25 gm Beeswax 2.7 gm Carbopol ® 934 q.s. 100.0 gm

Mixing is conducted with tile and spatula until a homogeneous creammixture is obtained having the prostaglandin uniformly dispersedthroughout the composition.

EXAMPLE 2

The procedure of Example 1 is repeated except that the followingcomponents are used:

Prostaglandin 0.25 gm Polyethylene glycol 400 37.5 gm 1,2,6-hexanetriol20.0 gm Polyethylene glycol 4000 q.s. 100.0 gm

A homogenous cream mixture is obtained.

EXAMPLE 3

The procedure of Example 1 is repeated except that the followingcomponents are used:

Prostaglandin 0.25 gm Polyethylene glycol 400 37.0 gm Polyethyleneglycol 400 monostearate 26.0 gm Polyethylene glycol 4000 q.s. 100.0 gm

A homogenous cream mixture is obtained.

EXAMPLE 4

The procedure of Example 1 is repeated except that the followingcomponents are used:

Prostaglandin 0.25 gm Polyethylene glycol 400 47.5 gm Cetyl Alcohol 5.0gm Polyethylene glycol 4000 q.s. 100.0 gm

A homogenous cream mixture is obtained.

EXAMPLE 5

An ointment formulation is prepared using a synthetic or semisyntheticprostaglandin. The ointment includes the following components:

Prostaglandin 0.25 gm Anhydrous lanolin 20.0 gm Mineral oil 25.0 gmWhite Petrolatum q.s. 100.0 gm

Mixing is conducted with tile and spatula until a homogeneous ointmentmixture is obtained having the prostaglandin uniformly dispersedthroughout the composition.

EXAMPLE 6

The procedure of Example 5 is repeated except that the followingcomponents are used:

Prostaglandin 0.25 gm Diisopropyl Adipate 19.95 gm White Petrolatum, USPq.s. 100.0 gm

A homogenous ointment mixture is obtained.

In the cream and ointment formulations described in Examples 1-6,optional ingredients can include materials such as antioxidants,viscosity modifiers (e.g., paraffin wax or lanolin wax), and topicalabsorption rate modifiers. The formulations may be administered usingthe clitoral application device of FIG. 1.

EXAMPLE 7

A vaginal suppository formulation is prepared using a synthetic orsemisynthetic prostaglandin. The suppository includes the followingcomponents:

Prostaglandin 0.25 gm Polyethylene glycol 400 37.0 gm Glycerol gelatin20.0 gm Polyethylene glycol 4000 q.s. 100.0 gm

The polyethylene glycol 400 solution containing prostaglandin is mixedwell with glycerol gelatin or similar suppository base such as macrogol,Witepsol®, or the like, with a mechanical mixing apparatus, and themixture is then cooled in a suppository mold.

EXAMPLE 8

Suppositories suitable for transurethral administration of a unit dosageof synthetic or semisynthetic prostaglandin are prepared. Apharmaceutical formulation containing a prostaglandin for transurethraladministration is prepared by mixing the selected prostaglandin withpolyethylene glycol, molecular weight (M_(w)) approximately 4000, andheating the mixture to a temperature just high enough to produce aprostaglandin-polymer melt. The prostaglandin-glycol mixture can then bepoured into a mold suitable to provide a prostaglandin suppository, andallowed to cool. The suppository so provided is a unit dosage formsuitable for transurethral administration. If desired, theprostaglandin-glycol mixture may be allowed to cool on the tip of a rodadapted to be inserted into the urethra.

EXAMPLE 9

The procedure of Example 8 is repeated, except that cocoa butter issubstituted for polyethylene glycol.

EXAMPLE 10

A prostaglandin-pharmaceutical formulation containing prostaglandin fortransurethral administration is prepared by dissolving a prostaglandinin a sufficient quantity of water. Glycerin (70%) is then added,followed by addition of Pharmagel A or B (20%). Suppositories are thenprepared as described in Example 8.

EXAMPLE 11

Individuals are assessed and pre-screened to assemble an experimentalgroup of subjects suffering from sexual dysfunction. The compositionsprepared in Examples 1-6, formulated with prostaglandin E₁, eachassessed in the experimental subjects for their ability to increaseuterine or vaginal epithelial blood flow. The formulations are appliedvaginally, and changes in blood flow or vaginal fluid production afterapplication of the vasodilating formulations are determined using knownmethods. Increase in vaginal epithelial blood flow is determined usingindirect methods such as photoplethysmography (Levin (1980) Clinics inObstet. Gynaecol. 7:213-252), heated oxygen electrode (Wagner et al.(1978), “Vaginal Fluid” in The Human Vagina, Evans et al. (eds.),Amsterdam: Elsevier/North Holland Biomedical Press, pp. 121-137), anddirect clearance of radioactive Xenon (Wagner et al. (1980) Obstet.Gynaecol. 56:621-624). Changes in vulvar blood flow are monitored usinglaser Doppler velocimetry (Sarrel, P. M. (1990) Obstet. Gynaecol.75:26S-32S).

Decreased vaginal dryness and/or dyspareunia are negatively correlatedwith vaginal blood flow rates, wherein increased blood flow to thevagina correlates with increased lubrication and decreased frequency andseverity of dyspareunia (Sarrel, P. M. (1990) Obstet. Gynaecol.75:26S-32S). Accordingly, vulvar blood flow after treatment is assessedusing laser Doppler velocimetry and compared to baseline levels.Increased vaginal lubrication as a result of treatment with thevasoactive formulations can also be assessed using the methods ofSemmens et al. (1982) J. Am. Med Assoc. 248:445-448. The compositions ofExamples 1-6, when assessed using such methods, are found tosubstantially increase blood flow to the vagina and vulvar area andalleviate vaginal dryness.

EXAMPLE 12

The method of Example 11 is repeated using the suppository formulationof Example 7. Substantially the same results are obtained.

EXAMPLE 13

The method of Example 11 is repeated, but the formulations are appliedtopically, to the vulvar area, instead of vaginally. Substantially thesame results are obtained.

EXAMPLE 14

The method of Example 11 is repeated using the urethral suppositories ofExamples 8, 9 and 10, and the compositions are administeredtransurethrally instead of vaginally. Substantially the same results areobtained.

What is claimed is:
 1. A method for treating sexual dysfunction in afemale individual, comprising administering to the vagina and/or vulvarregion of the individual therapeutically effective amounts of (a) aprostaglandin selected from the group consisting of naturally occurringprostaglandins, semisynthetic prostaglandin derivatives, syntheticprostaglandin derivatives, pharmacologically acceptable salts, esters,and inclusion complexes thereof, and combinations of any of theforegoing, and (b) an androgenic agent.
 2. The method of claim 1,wherein the prostaglandin is a naturally occurring prostaglandin or ahydrolyzable lower alkyl ester thereof.
 3. The method of claim 2,wherein the naturally occurring prostaglandin is selected from the groupconsisting of PGE₀, PGE₁, PGA₁, PGB₁, PGF_(1α), 19-hydroxy-PGA₁,19-hydroxy-PGB₁, PGE₂, PGA₂, PGB₂, 19-hydroxy-PGA₂, 19-hydroxy-PGB₂,PGE₃, PGF_(3α), PGI₂, hydrolyzable lower alkyl esters thereof, andcombinations of any of the foregoing.
 4. The method of claim 3, whereinthe naturally occurring prostaglandin is PGE₀.
 5. The method of claim 3,wherein the naturally occurring prostaglandin is PGE₁.
 6. The method ofclaim 3, wherein the naturally occurring prostaglandin is PGE₂.
 7. Themethod of claim 1, wherein the vasoactive agent is a syntheticprostaglandin derivative or a hydrolyzable lower alkyl ester thereof. 8.The method of claim 7, wherein the synthetic prostaglandin derivative isselected from the group consisting of carboprost tromethamine, dinoprosttromethamine, gemeprost, metenoprost, sulprostone and tiaprost.
 9. Themethod of claim 1, wherein the prostaglandin, the androgenic agent, orboth are contained within a delivery system selected to provide apredetermined agent release profile.
 10. The method of claim 9, whereinthe agent release profile is pulsatile.
 11. The method of claim 9,wherein the agent release profile is continuous.
 12. The method of claim9, wherein the agent release profile is cyclical.
 13. The method ofclaim 9, wherein the agent release profile is diurnal.
 14. The method ofclaim 1, wherein the prosraglandin and the androgenic agent arecontained within a single pharmaceutical formulation.
 15. The method ofclaim 14, wherein the formulation is administered vaginally.
 16. Themethod of claim 15, wherein the pharmaceutical formulation is in theform of an ointment, cream, gel, solid, solution, suspension, foam orliposomal composition.
 17. The method of claim 15, wherein thepharmaceutical formulation is contained within a vaginal ring, tampon,suppostory, sponge, pillow, puff, or osmotic pump system.
 18. The methodof claim 14, wherein the formulation is administered to the vulvar area.19. A method for improving vaginal muscle tone and tissue health in afemale individual, comprising vaginally administering to such individualtherapeutically effective amounts of (a) a prostaglandin selected fromthe group consisting of naturally occurring prostaglandins,semisynthetic prostaglandin derivatives, synthetic prostaglandinderivatives, pharmacologically acceptable salts, esters, and inclusioncomplexes thereof, and combinations of any of the foregoing, and (b) anandrogenic agent.
 20. A method for enhancing vaginal lubrication in afemale individual, comprising vaginally administering to such individualtherapeutically effective amounts of (a) a prostaglandin selected fromthe group consisting of naturally occurring prostaglandins,semisynthetic prostaglandin derivatives, synthetic prostaglandinderivatives, pharmacologically acceptable salts, esters, and inclusioncomplexes thereof and combinations of any of the foregoing, and (b) anandrogenic agent.
 21. The method of claim 1, wherein the androgenicagent is selected from the group consisting of androsterone,androsterone acetate, androsterone, androstenediol, androstenedione,ethylestrenol, oxandrolone, nandrolone, stanozolol, dromostanolone,testosterone, dehydroepiandrosterone, 5α-dihydrotestosterone, methyltestosterone, testolactone, oxymetholone, fluoxymesterone, andpharmaceutically acceptable esters thereof.
 22. The method of claim 21,wherein the androgenic agent is selected from the group consisting oftestosterone, 5α-dihydrotestosterone, and pharmaceutically acceptableesters thereof.
 23. The method of claim 22, wherein the androgenic agentis testosterone.
 24. The method of claim 22, wherein the androgenicagent is 5α-dihydrotestosterone.
 25. The method of claim 22, wherein theandrogenic agent is a testosterone ester.
 26. The method of claim 25,wherein the testosterone ester is selected from the group consisting oftestosterone enanthate, testosterone propionate, testosterone cypionate,testosterone phenylacetate, testosterone acetate, testosteroneisobutyrate, testosterone buciclate, testosterone heptanoate,testosterone decanoate, testosterone undecanoate, testosterone caprateand testosterone isocaprate.
 27. The method of claim 26, wherein thetestosterone ester is testosterone propionate.
 28. The method of claim22, wherein the androgenic agent is a 5α-dihydrotestosterone ester. 29.The method of claim 28, wherein the 5α-dihydrotestosterone ester isselected from the group consisting of the 5α-dihydrotestosteroneenanthate, 5α-dihydrotestosterone propionate, 5α-dihydrotestosteronecypionate, 5α-dihydrotestosterone phenylacetate, 5α-dihydrotestosteroneacetate, 5α-dihydrotestosterone isobutyrate, 5α-dihydrotestosteronebuciclate, 5α-dihydrotestosterone heptanoate, 5α-dihydrotestosteronedecanoate, 5α-dihydrotestosterone undecanoate, 5α-dihydrotestosteronecaprate and 5α-dihydrotestosterone isocaprate.
 30. The method of claim29, wherein the 5α-dihydrotestosterone ester is 5α-dihydrotestosteronepropionate.
 31. The method of claim 1, wherein the sexual dysfunction isan excitement stage dysfunction.
 32. The method of claim 30, wherein theexcitement stage dysfunction is touch sensation impairment.
 33. Themethod of claim 30, wherein the excitement stage dysfunction is loss ofclitoral sensation.
 34. The method of claim 30, wherein the excitementstage dysfunction is vaginal dryness.
 35. The method of claim 30,wherein the excitement stage dysfunction is dyspareunia.
 36. The methodof claim 18, wherein the prostaglandin is a naturally occurringprostaglandin or a hydrolyzable lower alkyl ester thereof.
 37. Themethod of claim 36, wherein the naturally occurring prostaglandin isselected from the group consisting of PGE₀, PGE₁, PGA₁, PGB₁, PGF_(1α),19-hydroxy-PGA₁, 19-hydroxy-PGB₁, PGE₂, PGA₂, PGB₂, 19-hydroxy-PGA₂,19-hydroxy-PGB₂, PGE₃, PGF_(3α), PGI₂, hydrolyzable lower alkyl estersthereof, and combinations of any of the foregoing.
 38. The method ofclaim 37, wherein the naturally occurring prostaglandin is PGE₀.
 39. Themethod of claim 37, wherein the naturally occurring prostaglandin isPGE₁.
 40. The method of claim 37, wherein the naturally occurringprostaglandin is PGE₂.
 41. The method of claim 19, wherein theprostaglandin is a synthetic prostaglandin derivative or a hydrolyzablelower alkyl ester thereof.
 42. The method of claim 41, wherein thesynthetic prostaglandin derivative is selected from the group consistingof carboprost tromethamine, dinoprost tromethamine, gemeprost,metenoprost, suiprostone and tiaprost.
 43. The method of claim 19,wherein the androgenic agent is selected from the group consisting ofandrosterone, androsterone acetate, androsterone, androstenediol,androstenedione, ethylestrenol, oxandrolone, nandrolone, stanozolol,dromostanolone, testosterone, dehydroepiandrosterone,5α-dihydrotestosterone, methyl testosterone, testolactone, oxymetholone,fluoxymesterone, and pharmaceutically acceptable esters thereof.
 44. Themethod of claim 43, wherein the androgenic agent is selected from thegroup consisting of testosterone, 5α-dihydrotestosterone, andpharmaceutically acceptable esters thereof.
 45. The method of claim 44,wherein the androgenic agent is testosterone.
 46. The method of claim44, wherein the androgenic agent is 5α-dihydrotestosterone.
 47. Themethod of claim 45, wherein the androgenic agent is a testosteroneester.
 48. The method of claim 47, wherein the testosterone ester isselected from the group consisting of testosterone enanthate,testosterone propionate, testosterone cypionate, testosteronephenylacetate, testosterone acetate, testosterone isobutyrate,testosterone buciclate, testosterone heptanoate, testosterone decanoate,testosterone undecanoate, testosterone caprate and testosteroneisocaprate.
 49. The method of claim 48, wherein the testosterone esteris testosterone propionate.
 50. The method of claim 44, wherein theandrogenic agent is a 5α-dihydrotestosterone ester.
 51. The method ofclaim 50, wherein the 5α-dihydrotestosterone ester is selected from thegroup consisting of the 5α-dihydrotestosterone enanthate,5α-dihydrotestosterone propionate, 5α-dihydrotestosterone cypionate,5α-dihydrotestosterone phenylacetate, 5α-dihydrotestosterone acetate,5α-dihydrotestosterone isobutyrate, 5α-.dihydrotestosterone buciclate,5α-dihydrotestosterone heptanoate, 5α-dihydrotestosterone decanoate,5α-dihydrotestosterone undecanoate, 5α-dihydrotestosterone caprate and5α-dihydrotestosterone isocaprate.
 52. The method of claim 50, whereinthe 5α-dihydrotestosterone ester is 5α-dihydrotestosterone propionate.53. The method of claim 20, wherein the prostaglandin is a naturallyoccurring prostaglandin or a hydrolyzable lower alkyl ester thereof. 54.The method of claim 53, wherein the naturally occurring prostaglandin isselected from the group consisting of PGE₀, PGE₁, PGA₁, PGB₁, PGF_(1α),19-hydroxy-PGA₁, 19-hydroxy-PGB₁, PGE₂, PGA₂, PGB₂, 19-hydroxy-PGA₂,19-hydroxy-PGB₂, PGE₃, PGF_(3α), PGI₂, hydrolyzable lower alkyl estersthereof, and combinations of any of the foregoing.
 55. The method ofclaim 54, wherein the naturally occurring prostaglandin is PGE₀.
 56. Themethod of claim 54, wherein the naturally occurring pro staglandin isPGE₁.
 57. The method of claim 54, wherein the naturally occurringprostaglandin is PGE₂.
 58. The method of claim 20, wherein theprostaglandin is a synthetic prostaglandin derivative or a hydrolyzablelower alkyl ester thereof
 59. The method of claim 58, wherein thesynthetic prostaglandin derivative is selected from the group consistingof carboprost tromethamine, dinoprost tromethamine, gemeprost,metenoprost, sulprostone and tiaprost.
 60. The method of claim 20,wherein the androgenic agent is selected from the group consisting ofandrosterone, androsterone acetate, androsterone, androstenediol,androstenedione, ethylestrenol, oxandrolone, nandrolone, stanozolol,dromostanolone, testosterone, dehydroepiandrosterone,5α-dihydrotestosterone, methyl testosterone, testolactone, oxymetholone,fluoxymesterone, and pharmaceutically acceptable esters thereof.
 61. Themethod of claim 60, wherein the androgenic agent is selected from thegroup consisting of testosterone, 5α-dihydrotestosterone, andpharmaceutically acceptable esters thereof.
 62. The method of claim 61,wherein the androgenic agent is testosterone.
 63. The method of claim61, wherein the androgenic agent is 5α-dihydrotestosterone.
 64. Themethod of claim 61, wherein the androgenic agent is a testosteroneester.
 65. The method of claim 64, wherein the testosterone ester isselected from the group consisting of testosterone enanthate,testosterone propionate, testosterone cypionate, testosteronephenylacetate, testosterone acetate, testosterone isobutyrate,testosterone buciclate, testosterone heptanoate, testosterone decanoate,testosterone undecanoate, testosterone caprate and testosteroneisocaprate.
 66. The method of claim 65, wherein the testosterone esteris testosterone propionate.
 67. The method of claim 61, wherein theandrogenic agent is a 5α-dihydrotestosterone ester.
 68. The method ofclaim 67, wherein the 5α-dihydrotestosterone ester is selected from thegroup consisting of the 5α-dihydrotestosterone enanthate,5α-dihyclrotestosterone propionate, 5α-dihydrotestosterone cypionate,5α-dihydrotestosterone phenylacetate, 5α-dihydrotestosterone acetate,5α-dihydrotestosterone isobutyrate, 5α-dihydrotestosterone buciclate,5α-dihydrotestosterone heptanoate, 5α-dihydrotestosterone decanoate,5α-dihydrotestosterone undecanoate, 5α-dihydrotestosterone caprate and5α-dihydrotestosterone isocaprate.
 69. The method of claim 68, whereinthe 5α-dihydrotestosterone ester is 5α-dihydrotestosterone propionate.